RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors

  • J Med Chem. 2025 Nov 13;68(21):22196-22215. doi: 10.1021/acs.jmedchem.5c00551.
Gurushankar Chandramouly  1 ,  William Fried  2 ,  John Gordon  3 ,  Douglas Ralph  1 ,  Channita Keuk  3 ,  Sangeeta Kumari  4 ,  Mercy Ramanjulu  5 ,  William Auerbacher  1 ,  Leonid Minakhin  1 ,  Taylor Tredinnick  1 ,  Bernadette Tiberi  1 ,  George Morton  4 ,  Robert Betsch  6 ,  Kathy Q Cai  6 ,  Umeshkumar M Vekariya  3 ,  Mrityunjay Tyagi  1 ,  Tomasz Skorski  6  3 ,  Sergey Karakashev  3 ,  Neil Johnson  6 ,  Wayne E Childers Jr  5  4 ,  Xiaojiang S Chen  2  5 ,  Richard T Pomerantz  1  5
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, United States.
  • 2. Molecular and Computational Biology, USC Dornsife Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, United States.
  • 3. Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140, United States.
  • 4. Temple University, School of Pharmacy, Philadelphia, Pennsylvania 19140, United States.
  • 5. Recombination Therapeutics, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania 18902, United States.
  • 6. Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States.
PMID: 41124685 DOI: 10.1021/acs.jmedchem.5c00551
Abstract

DNA Polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic Cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like properties of RTx-303. Notably, RTx-303 exhibits significantly higher cellular potency than previously developed Polθ-pol inhibitors and strongly potentiates PARPi in BRCA1/2 mutant cells and patient-derived xenograft models. The superior potency, robust pharmacological activity, and high tolerability of RTx-303 warrant further development as a Polθ-pol inhibitor drug candidate.

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